Week 6 Random Flashcards
1
Q
Which embyonic layer gives rise to the epihelium? connective tissue?
A
E: Ectoderm, Mesoderm, Endoderm
C: Mesoderm, Ectoderm (head)
2
Q
Where is epithelium found?
A
It lines all cavities and outside surfaces.
3
Q
What are the functions of epithelia?
A
Protection
Transcellular Transport (e.g. vessicles for IgA, carrier protein aa & glucose, and diffusion of oxygen in alveoli)
Secretion (exocytosis e.g. hormones)
Absorption (endocytosis e.g. PCT in kidney)
Selective Permeability
Sensory Organ (e.g. taste buds, retina, hair cells)
4
Q
What is another name for intermediate filaments?
A
Cytokeratin / Tonofilaments
5
Q
Characteristic of epithelium
A
Polarized
Intermediate Filaments
Connected by junctions that form sheets
Separated by basement membrane
Avascular
Rapid regeneration
6
Q
Simple Squamous Epithelium
Location and Function
A
Pulmonary aveoli (gaseous exchange)
parietal layer of Bowman’s capsule (fluid exchange)
loop of Henle
inner and middle ear
Endothelium: blood and lympathic vessels (lubrication)
Mesothelium: pleural and peritoneal cavities (reducing friction)
7
Q
Simple Cuboidal Epithelium
Location and Function
A
Ducts
Distal tubule in kidney (absorption)
Glands (secretion)
Surface of ovary (protection)
8
Q
Simple Columnar Epithelium
Location and Example
A
Oviduct (transport)
Efferentes of testis (transport)
Uterus (secretion)
Small bronchi
Digestive tract (secretion/absorption)
Small gallbladder and excretory ducts in some glands (protection)
9
Q
Simple Pseudostratified Epithelium
Location and Example
A
Trachea (secretion/absorption)
Primary bronchi
Epididymis and ductos deferens
Auditory tube (protection)
Tympanic cavity
Lacrimal Sac
Male urethra (transportaion/lubrication)
Large excretory duct
10
Q
Two types of epithelium
A
Endothelium: lining of blood vessels and lympathics
Mesothelium: lining of body cavities
11
Q
Simple vs. Stratified Epithelium
A
In simple epithelium, all cells lie upon the basement membrane.
12
Q
Two types of stratified squamous epithelium
A
nonkeratinized stratified / moist (associated with mucosa) - have alive cells at the surface
keratinized - have denucleated cells at the surface
13
Q
Stratified Squamous (non-keratinized) Epithelium
Location and Examples
A
Functions: protection & secretion
Examples: Mouth, Epiglottis, Escophagus, Vocal cords, and Vagina
14
Q
Stratified Squamous (Keratinized) Epithelium
Location and Function
A
Epidermis of skin
Protection
15
Q
Cuboidal Stratified Epithelium
Location and Function
A
Lining ducts of sweat glands
Absorption and secretion
16
Q
Stratified Columnar Epithelium
A
Conjuctiva of eye, some large exretory ducts, portion of male urethra
Secretion, absorption, protection
17
Q
Transitional Epithelium
A
Linig of urinary passages from renal calyces to the urethra
Protection and distensible
18
Q
Functions of basement membrane
A
Anchoring
Vascular layer
Transcellular transport
19
Q
What are microenviroments in epithelial cell?
A
Apical, Laterl, and Basement part.
20
Q
Surface modifications
Types, Size, Location, and Function
A
Microvilli (GI tract) “striated border” , 1 um, absoroptin
Microvilli (Kidney) “bursh border”, 1 um, absorption
Stereocilia (Epididymis, DD, innear ear), 2um, absorption
Cilia (Respiratory, Oviduct), 10um, movement of stuff
21
Q
What supports microvilli?
What is the purpose of microvilli?
Are microvilli pernament?
A
Actin
Increase surface area
Appear and disapear quickly
22
Q
Stereocilia vs. Cilia
A
Cilia are larger and less dense
Stereocilia are smaller and more dense
23
Q
Celiac sprue
A
Sensitivity to gluten (component of wheat flour)
Due to loss of microvilli in small intestine
= less absorption and osmotic diarrhea
24
Q
Kartagener’s Syndrome
Immobile Cilia Syndrome
A
Dynein arms missing = cilia do not move
Chronic respiratory difficulty including bronchitis and sinusitis
25
Types of intermediate filaments
Keratin (epithelial cells)
Desmin (muscle cells)
Vimentin (fibroblast, endothelail, chondroblast, macrophage, mesenchymal)
Glial fibrillary acid protein (astrocytes)
Neurofilaments (neurons)
Lamins A, B, C (nuclear lamin of all cells)
26
Tunctional complex (terminal bar)
Other junctions?
Complex of structures
Zona occludens ZO (tight junction), belt-like, no cystoskeleton [functional]
Zona adherens ZA (adhesion belt), belt-like, actin - cadherin (CAMs) [mechanical]
Macula adherens MA (desmosome), spot, keratin - cadherin (CAMs) [mechanical]
Other
Gap Junctions GJ, spot, connexins forming connexons no cytoskeletom [functional]
Hemidesmosomes, spot, kerain - basement membrane [mechanical]
27
Basal Membrane subcomponents
What are these subcomponents are made of?
Basal lamina: lamina lucida (laminin, fibronectin, GAG) lamina densa (type IV collagen)
Reticular lamina (type IV and type VII collagen)
28
What is the shape of the basal membrane?
Infoldings with mitochondria
29
Basement Membrane types
Epithelium conntected to connective tissues (most common)
Epithelium connected to epithelium (aveoli of lung / glomerulus)
30
Serosa components
Mesothelium that lies on the connective tissue
31
Mucosa layers
Epithelium w/or w/o glands
Basement membrane
Lamina propia
Muscularis mucosae
32
Intestinal wall layers
Mucosa
Submucosa
Muscularis
Serosa
33
Exocrine gland by types of secretion
Serous (parotid, exocrine pancreas) = protein rich / carbhodyrate poor
Mucous (golbet cells) = carbohydrate rich / protein poor
Mixed (submandibular, sublingual) mix groups of cells
34
Exocrine glands
Secretory mechanisms
Merocrine (eccrine)
Apocrine
Holocrine
35
Most common gland mechanism?
Merocrine (sweat gland)
36
What layer are glands derived from?
Epithelium
37
What is the most common unicellular exocrine gland?
Goblet cell
38
What is the shape of the typical salivary exocrine gland?
Compound tubuloaveolar
39
Classification of connective tissue
Proper: loose, dense, adipose
Bone
Cartilage
Blood
Lymph
40
Three components of connective tissue
Ground bustance
Fibers
Cells
(GS + fibers = ECM)
41
Functions of connective tissue
Mechanical support
Protection of soft tissues
Physiological support (nerves, fluids, metabolites)
Storage (fat)
Immune defence
Repair of injuries
42
Composition of ground substance
Function of components
Gyclosaminoglycans (strongly hydrated = reistant to compression, negative charge = repulsive and slippery)
Proteoglycans (trap water, occupy space,
Glycoproteins (cell adhesions)
43
Functions of ground susbtance
Traps water (fullnes to skin, protection, reduces fluid loss, limits pathogenic invasion)
Anchors
Acts as a charge and size barrier (regulates access to cells)
Contributes to the physical properties of a connective tissue (reinforced concrete)
Regulates morphogenesis (migration, growth factor activation)
Facilitates cell migration
44
Which GAG is non-sulfated?
Hyaluronan
1 g can absorb 48 g of water
45
Distrubances of ground susbtance
Improper nutrient/waste management
Improper tissue development
Improper tissue growth
Cell malfunction: GAG accumulation in lysozomes (mucopolysaccharidoses)
46
Three types of fibers seen at the light microscope level
Reticular fibers (silver stain)
Elastic fibers (special stain)
Collagen (H&E)
\* sometimes not seet because they are embeded in a ground susbtance
47
Types of collagen
Type I = stiff (bone, skin, tendon, dentin, fibrocartilage)
Type II = jelly (hyaline and elastic cartilage, viterous humor)
Type III = delicate (lymphatic tissue, adipose, liver, cardicascular, lung)
Type IV = filtration/support (basal lamina)
48
Diseases assocaited with collagen
49
Fibrillin
Family of proteins which provides the scaffolding for the deposition of the elastin core
50
Marfan syndrome cause
Mutation in fibrillin gene
51
Connecttive Tissue Cells
Fixed (resident) vs. Free (transient)
Fixed are derived from mesenchymal cell
Free are derived from hemopoetic cell
52
Pericytes
Stem cells for CT
Role in angiogenesis and hypercullar obsesity
53
Fibroblasts
Produce fibers and ground system
Found in embryonic, repaired, and traumatized tissues
54
Organization of elastic fibers
Fibers
Networks
Membrane
55
Plasma cells
Scattered in CT, but highly present in inflamation
Clock nucleus
56
Macrophages
Differentiate upon entry into the CT
Types: fixed and free
Part of the Mononuclear Phagoctic system (MPS)
APC
Phagocytosis may be immune or non-immune mediated
57
Mast cells
Possess granules containg histamine, heparin, and others considered to be primary mediators
Degranulate with the secondary exposure to an antigen (allergen)
58
Primary vs. Secondary response in Mast cells
Primary
IgE binding to Fc receptors
Secondary Response (in Color)
Antigen crosslinks IgE molecules
Granules released (primary mediators)
Secondary mediators released
59
White Fat cells
90% triglyceride
Storage, insulation, protection
Hormone production (leptin and adiponectin)
Number is determined perinatally
Cancers: Lipomas and Liposarcomas
60
Brown Fat cells
Many mitochondria
Specifc locations neck and inter-scapular regions of infant
Nerve are associated with brown fat (white fat does not have)
Thermogenesis by fatty acids oxidation
61
Classification of connective tissue
Loose connective tissue
Dense regular connective tissue
Densre irregular connective tissue
62
Cancer cells must have two heritable properites:
1. Defiance of normal cell controls on division
2. Invasion and colonization of foreign tissues
63
Karposi's sarcoma
Malignant tumor of the connective tissue.
Often associated with AIDS
AIDS related Kaposi's sarcoma is mediated by HIV, immune system suppression, and human herpesvirus-8 (HHV-8)
64
Philadephia chromosome
9-22 translocation
increases risk of developing CML (chronic myolegenous leukemia)
DNA break is always the same
Caricongenesis is linked with mutagenesis
65
Carcinogens that may cause mutations
Chemical (point mutations in DNA)
Ionazing radiation X-ray (cause translocation and breakage)
Transforming viruses (introduction of foreign DNA)
66
Relationship of exposure to carinogenesis
example of 2-naphtylamine
proportional to years of exposure
delayed onset
67
General steps in carcinogenesis
Mono layer propagation
Multi layer
Invasion
68
Characteristics of cancer cells
1. Disregard cell proliferation internal and external signals
2. Avoid apoptosis
3. Circumvent limitations to proliferation (senesence, differentiation)
4. Geneticall unstable (e.g. p53)
5. Escape from their origin
6. Survive and profilerate in foreign sites
7. Mantained by cancer stem cells
69
Two classes of genes assocaited with carcenogenesis
Oncogenes (GOF)
Tumor Supressor (LOF)
70
Example of Tumor Suppresor
71
Example of Oncogene
72
BAD mechanism and inactivation
73
Two types of signalling pathways
Pathway to drive cell cycle
Pathway to aquire nutriets
74
Warburg effect
non-Hodking lymphoma NHL and fluorodeoxyglucose
High FDG uptake indicates cells with unusually active
glucose uptake and metabolism, a characteristic of tumors.
75
Three categories of genetic alterations in cancers
Point mutations / deletion (e.g. Ras, EGF receptor)
Gene amplification (src, myc)
Chromosome Rearrangement (myc in Bukitt's lymphoma or Abl in CML)
76
p53
Tumor Suppressor
Transciption factor
p53 mutations found in 50% of cancers
77
Gleevec
Specific inhibitor (prevent phsophorylation of Bcr-Abl-substrate complex
Prevent leukemia
78
Iressa
Selective inhibitor of EGFR tyrosine kinease
Also called Her1 or ErbB-1
Effective against breast cancers
79
Salirasib
Competitive inhibitor of ras binding to galectin
Ras mutations are found in 90% of all pancreatic cancers
80
Zelboraf
targets the V600E mutation in Raf that constitutively activates Raf
Found in 1/2 of melanoma
81
Cancer name derived from
Crab
Greek KARKINOS
crab-like extensions
82
Properties of cancer
Uncontrolled Growth
Invasion and Metastasis
Clonal Dominance
Loss of Differentiation
83
Benign. vs Malignant
Benign: unrestrained growth; circumscribed border; rarely kills
Malignant: unrestrained growth; invasion; metastais and kills host
84
Definition of invasion
Active migration of neoplastic cells out of their tissue of origin and across host tissue boundaries
85
Definition of metastasis
(1) A secondary tumor colony discontinuous from the primary tumor
(2) Arising from a tumor cell translocated from the primary tumor
86
Definitions:
Tumor
Neoplasia
Oncology
Cancer
Tumor (swelling or mass) nonspecific suffic "\_oma"
Neoplasia (new growth)
Oncology (Gr onkos = mass, bulk)
Cancer (crab; appearance vs. behavior)
87
Metaplasia
A reversible histological event in which one adult cell type is changed into another adult cell type
88
Atypia
A histological or cytological event non-conforming to an established type.
89
Malignant vs. Benign type
Epithelium vs. Mesenchymal origin
Nomencalture
MESENCHYMAL
**Benign "\_oma"** e.g. adenoma
**Malignant "\_sarcoma" **e.g. liposarcoma
EPITHELIAL
**Benign "\_adenoma"**
**Malignant "\_carcinoma"** e.g. carcinoma
90
Tumor additional descriptive terms
Papilloma
91
Exceptions to cancer nomenclature
Non-benign: hepatoma, lymphoma, melanoma, mesothelioma, seminoma
Not neoplasm: hamartoma (disorganized overgrowth of normal tissue) choristoma (ectopic mass of non-neoplastic tissue abnormal for site)
Neoplasm of bone marrow origin "-emia" (e.g. leukemia)
Neoplasm of embryonic origin "-blastoma" (e.g. neuroblastoma)
92
Events related to tumor progression
Changes
1. Genetic (ONC, TS)
2. Epigenetic
93
Angiogenesis
Required for tumor progression 1 to 2 mm
Aid metastasis
94
Size / Aggresivenes / Metastatis
The more aggressive cancers metastasize at smaller size.
95
Benign vs. Malignant:
Uncontrolled proliferation
Monoclonality
Loss of differentiation
Genetic alterations
Angiogenesis
Invasion and metastasis
96
Cancer therapy
Surgery
Radiotherapy
Chemotherapy
Immunotherapy
97
Does the "invasion" as a trangression of the basement membrane apply to sarcomas?
No.
It is more difficult to determine invasion in sarcomas and distinguish sarcomas from benign mesenchymal tumors for that reason.
We must rely on other pathological findings like mitoses, proliferation index, size and necrosis.
98
Multistep nature of tumor progression
Normal duct
Intraductal hyperplasia
Inraductal hyperplasia with atypia
Intraductal carinoma in situ
Invasive carcinoma
99
Grading: 2 types
Tissue pattern: well, moderately, and poorly differentiated
Nuclear features: low, intermedaite, and high
I to IV
100
Cancer staging
A measurment of degree of invasion and metastasis
Tumor Lymph Node Metastases (TNM), AJC
101
Three routes for metastasis
Lymphatic (lymph nodes)
Hematogenous (lung, liver, brain, bone marrow and adrenals)
Transcoelomic spread (peritoneal, pleural, pericardial and subarachnoid spaces
102
Metastasis route for carcinomas vs. Sarcomas
Carcinomas: lymph route
Sarcomas: blood
103
Cancer heterogeneity
Mutant subclones are heterogeneous with respect to invasiveness, metastatic ablility, antigenicity and responsiveness to chemotherapy
104
–Invasion and interaction with the extracellular matrix (ECM) is divided into 4 steps.
1. Less cohesive (e-cadherins reduced)
2. Attachement to matrix (laminin and fibronectin)
3. Degradation (Metalloproteinases: collagenases and plasmin)
4. Migrations (cytokines and cleavage products of ECM)
105
Dissemination and Homing of cancer cells
Dissemination: Can circulate with leukocytes/platelets or alone
Homing: depends on vascular/lymphatic drainage, enhanced by adhesion molecules, proteases may inhibit
106
Soild Seed Hypothesis of Paget
107
Anatomical planes
Transverse plane (longitudinal axis)
Coronal/frontal plane (saggital axis)
Saggital plane (frontal axis)
Mid-saggital / Median plane
108
Joints three types
1. Synovial joint
2. Fibrous joints
3. Cartilaginous joints
109
Synovial joint characteristics
Most common
Freely movable \* not always
Lined by synovial membrane
Joint cavity opposed by articular cartilage (hyaline/fibrocaritlage)
Synovial membrane secretes synovial fluid
110
Fibrous joint charactersitics
Held by fibrous tissue e.g. suture, intrerosseous membrane
Suture = fibrous joint
111
Cartilaginous joint charactersitics
Held by cartilage e.g. epiphyseal plate and intervertebral discs (fibrocaritlage)
112
Label structures in joints
1. Periosteum
2. Ligament
3. Fibrous capsule
4. Synovial membrane
3+4 = Articular capsule
5. Compact bone
6. Femur
7. Join cavity (with synovial fluid)
8 Articular cartilage
9. Synovial membrane
10. Meniscus
11. Tibia
12. Infrapatellar fat pad
113
Label epidermis
1. Hair
2. Afferent nerve ending
3. Arrector muscle of hair
4. Collagen and elastic fibers
5. Sebaceous gland
6. Hair follice
7. Fat
8. Cytaneous nerve
9. Lymphatic vessel
10. Superficial blood vessels
11. Skin ligament (retinaculum cutis)
12. Sweat gland
13. Muscle
14. Deep fascia
15. Subcutaneous tissue (superficial facia)
16. Dermis
17. Epidermis
114
What determines stiffness of skin
Skin ligaments
115
Superficial Fascia characteristics
Fat
deep facia \<-\> Ligaments \<-\> dermis
Insulator
Protection for bony prominences
Blood vessels, nerves, and lymphatics
Glandular portion of sweat glands
116
What separates muscle/bones?
Deep facia
Muscles / bones are in capsules
117
Deep Fascia characterstics
Dense irregulat connective tissue
Attached by the ligaments to skin
Contacts muscle
Continuous with nerve
Connected to periosteum
Aids in moving the blood (muscle compartmentalization)
118
Aponeurosis
Layers of flat broad tendons
119
Thoraxs compnents
opened superiorly? opened inferiorly?
Ribs, sterum, cartilage, vertebra
Both open but diaphragm separates from abdominal cavity
120
Is nipple a good measure of the position of T4? What about dermatome that originated from T4?
No. Yes.
121
How far does respiration pushes diaphgram?
Deep expiration = 4th rib
Normal expiration = 6th rib
122
Costodiaphragmatic recess
A potential space in the pleural cavity, at the posteriormost tips of the cavity, located at the junction of the costal pleura and diaphragmatic pleura.
The lungs expand into this recess during forced inspiration, however the recess never fills completely. During expiration, it contains no lung tissue, only pleural fluid.
123
Heart location estimate
Between two joints of sternum body (around T4 and T9)
124
Angle of Louie clinical application?
Heart sounds
125
Is first rib palpable?
No
126
Most fracured place in a rib?
Anterior to the angle
127
Clinical importance of 2nd intercostal space
Intercostal brachial nerve = pain in upper limb in case of heart attack
128
What is facet?
Smooth surface that allows articulation
129
Surface landmarks (lines)
Scapular (midclavicular) line
Sternal line
Posterior/Mid/Anterior axillary line
130
Pectus Excavatum
Rapid growth of cartilage that pushes the sternum backwards. Is surgically repairable.
131
Costochondritis
Pain at the junction of the costal cartilage with the sternum. This pain is generally reproducible by pressure on the location.
You can reproduce this pain by pushing, but you cannot reproduce the pain caused by heart attack.
132
Deep fascia synonym
Investing fascia
133
Location of the breast
Between the 2nd and 6th ribs
From the **lateral border** of sternum to **midaxillary line**
Separated by **retromammary space** between deep (investing facia) from pectoralis major
134
Suspensory ligament synomyms
Cooper's ligament
Retinacula cutis
135
What is the breast size determined by in non-lactating breast?
The amount of fat surrounding the glandular tissue
136
When does the glandular tissue in breast develop?
Puberty
Fat deposition occurs
Lactiferous ducts give rise to 15-20 lobes of glandular tissue. These lobes further divide into lobules.
137
How many lobes drain into a duct?
How many ducts drain into a sinus?
15-20
12-15
138
Does the mechanism sucking (low pressure) releases milk?
No. The response releases the milk accumulated in sinuses.
139
Direction of the lymph originating from breast
To the other breast
To parasternal nodes
Down to the liver
To interpectoral nodes
To posterior axillary (subscapular) nodes (most likely)
140
Sentinel nodes
The first draining node
141
Which nodes are sentinel nodes for the breast?
Axillary
Interpectoral
142
Right versus Left side Lymph Drainage
One thoracic duct (left) dumps to left subclavian
Right lymphatic duct empties to equivalent two structures on right side
143
Polythelia
Multiple nipples
144
Location of breast augumentation
old : subglandular
new : submuscular
145
Gynecomastia
is the growth of abnormally large breasts in males.
146
Where does the neurovascular bunlde lines in ribs?
Between two deepest layers:
Innermost intercostal muscle
Internal intercostal muscle
147
Why intercostal veins do not go to vena cava?
There is no vena cava around heart
148
Accessory respiratory muscle
Any muscle attaching to the ribs or sternum has the potential to act as an accessory respiratory muscle by either elevating or depressing the ribs.
pectoralis major and minor, the scalenes, the serratus posterior and serratus anterior and the levator costarum
abdominal in forced respiration
149
Values for the skin
Skin is the largest organ of the body
8-10 pound
1. 6-2 m2
0. 5-4mm thickness 0.5 eye lids 4mm palms
150
Tension lines (langer lines)
The dermis contains a dense network of interlacing collagen and elastic fibers. These **fibers provide** skin **tone** and account for the strength and toughness of the skin. The predominant **pattern** and direction of the fibers **determines** the characteristic **tension and wrinkle** lines in the skin.
Elastic fibers deteriorate with age.
151
Breast metastases destination
Bone 80% (osteolytic metastases associated with hypercalcemia, bone pain, and fractures)
CSN particullary brain 20%
152
Herpes Zoster (Shingles)
An inflammatory skin disease caused by
Herpes simplex virus or varicella-zoster (chickenpox) virus (VZV).
It produces painful eruptions of groups of deep-seated vesicles
Herpes zoster is primarily a viral disease of the spinal ganglia (dorsal root ganglia). It is primarily a sensory neuropathy, although (in rare cases) muscular weakness can also occur.
153
What is the major cause of cell death?
Programmed cell death
154
Necrosis vs. Apoptosis
Cell size: swelling / shrinkage
Nucleus: disintegrate / chromatin condensation and fragmentation
Plasma membrane: distrupted / intact
Cellular content: enzymatic digestion / intact
adjacent inflammation: frequent / no (phagocytosis)
155
Eat me signals on cell surface for
engulfemt and phagocytsis
Flipped-out phosphatidylserine
Thrombospondin
Adhesive glycoprotein
Natural antibodies, and proteins of complement system, notably C1q
Soluble factors
156
Does phagocytosis cause inflammation?
No
157
Initiation of apoptosis 2 pathways
Mitochondrial pathway (intrinsic signals)
Death receptor–initiated pathway (extrinsic signals)
158
What executes apoptosis?
Caspase cascade
159
Caspase
name?
Caspase: cysteine-aspartic proteases
Possesses cysteine residue in active site
Caspase cleaves following aspartate residue in target peptide
Nearly 100 different cell target proteins (nuclar lamins, acin, myosin, golgi matrix proteins)
160
Apoptotic caspases
Initiatior
Executioner
Initiatior: 2,8, 9, 10
Executioner 3, 6, 7
161
Mitochondrial (intrinsic) pathway
**Bcl-2** family **act at** the **mitochondria**
**Cytochrome c released** from mitochondria **triggers caspase** activation
162
Intrinsic pathway: release of cytochrome C
163
Blc2 family examples
(regulator) anti-apoptotic Bcl2 protein: Bcl2, Bcl-X
(effector/channel) pro-apoptotic: Bak, Bax
(sensor) pro-apoptotic: Bad, Bim, Bid, Puma, Nox
164
What domain mediates binding between proapoptotic and antiapoptotic protein forming heterodimers?
BH3
165
Intrinsic pathway: controlling mitochonrial release of anti-IAP
Caspases are also regulated by the IAP (inhibitor of apoptosis) to prevent spontaneously cleaved caspases
Triggers apoptosome assembly that activates caspase cascade
166
Apoptosome assembly
**Cytochrome** c **binds Apaf1** (apoptosis-activating factor-1), causing it to hydrolyze its bound **dATP-dADP**
**replacement** of the **dADP** with **dATP** -\> **aggregation**
**Heptameric apoptosome**
**Recruits procaspase-9** through **caspase recruitment domain** (**CARD**) on each protein
Caspase cascade
167
p53 mediates apoptosis
When **DNA damage** is too extensive to repair, **ataxia telangiectasia mutated (ATM)** and **Chk2** protein kinases **phosphorylate**/activate **p53** tumor suppressor protein
- \> Cdk inhibitor **p21**, which inhibits Cdk2/cyclin E complexes, **halting cell cycle** progression in G1 (**cell cycle arrest**).
- \> **BH3-only** proteins **PUMA** and **Noxa**, which activate BH123 proteins Bax and Bak, leading to **mitochondrial release** of cytochrome c and activation of caspase-9 (**apoptosis**).
Mediates both cell cycle arrest and apoptosis
168
Extrinsic death receptor
**Death ligands**: **Tumor necrosis factor (TNF)** family of signal proteins (Fas ligand).
**Death receptors**: TNF family receptors (**Fas receptor**).
These receptors directly **activate** a distinct initiator caspases, **caspase-8 and/or -10**.
169
Extrinsic or death receptor initiated pathway
**Killer T cell-induced** apoptosis via **Fas** death **receptor**
**TNF and other cell death receptor** ligands consist of three polypeptide chains, so their binding to cell death receptors induces receptor **trimerization**.
FADD + proscaspase = DISC
**Caspase-8** is recruited to the receptor and activated via interaction with adaptor molecules. Once activated, c**aspase-8** cleaves and activates **effector caspases** (the extrinsic pathway of apoptosis).
In addition, **caspase-8** **cleaves** the **BH3-only** protein **Bid**, which activates the **intrinsic pathway** of apoptosis, leading to caspase-9 activation.
170
How cells are renewed?
**Most differentiated** cells are are **no** longer able to **proliferate**. Following injury, these cells are **replaced** by self-renewing **stem cells**.
Some differentiated cells that are arrested in G0 stage of the cell cycle retain the ability to resume proliferation as needed
171
Examples of cells proliferating
1) **Vascular Endothelial Growth Factor VEGF **(released by tissue deprived of oxygen and acting on endothelial cells)
2) Epithelial cells (after liver removed during surgery)
3) **Platelet Derived Growth Factor PDGF** (cut wound)
172
What is hyperplasia/hypertrophy?
dedifferentiation and growth
173
Assymetric divison
**stem cells** produce **one daughter** cell that remains continues proliferating indefinitely, and **one progenitor** cell that further divides and terminally differentiates.
## Footnote
*blood cells, sperm, epithelial cells of skin, liver, and lining digestive tract, skeletal muscle myosatellite cells, neural stem cells, and cardiac stem cells.*
174
Renewal of the intestinal epithelium
Intestinal epithelial cells are exposed to harsh environment and **live** only a **few days** before they die by apoptosis
These cells are **replaced by** slowly-dividing **stem cells in** the intestinal **crypts**
**Stem** cells **give rise** to a population of **transit-amplifying cells**, which proliferate for **3-4 divisions** and **then differentiate into** the three types of the colon surface epithelium (**absorptive epithelial** cells and two secretory cells, called **goblet** cells and **enteroendocrine** cells).
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Adult stem cells therapy
ex. hematopoietic stem cells / skin epithelial stem cells
Advantage: eleminates potential complication of graft rejection
Disadvantage: technical problems, not all tissue types, lack of pluripotency
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Embryonic stem cells
Derived from the inner cell mass of blastocyst
Advantages: ES pure stem cell; pluripotent; successful clinical transplanation
Disadvantage: cell culture conditions to obstain specific tissue; ethics
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Somatic cell nuclear transfer vs. Therapeutic cloning
Somatic cell nuclear transfer (dolly; injecting nucleus into the egg)
Therapeutic cloning (growin organs; injecting nucles to the egg of the same person)
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Induced pluripotent stem (iPS) cells
**iPS cells**: **pluripotent stem cells artificially derived** from a **non**-**pluripotent** cell - typically an adult somatic cell - by inducing a "forced" expression of specific genes.
Advantages: pluripotency; no tissue rejection; research
Disadvatage: technique not established; causing cancers
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Too much vs. too little apoptosis
Too little: Cancers, autoimmune, hematological diseases
Too much: neurodegenrative diseases; infection; ischemia; autoimme disease
